Erythropoiesis will be characterized during ontogeny and in patients with hematologic disease. The hypothesis is that erythrocytes produced in fetuses differ from the fetal-like erythrocytes produced during stress erythropoiesis, in bone marrow failure or myeloproliferative diseases, and in hemoglobinopathies. The difference between the fetal and fetal-like erythrocytes is in the degree of "fetalness", i.e., levels of Hb F, size, i antigen, etc. Treatment of patients with hemoglobinopathies such as sickle cell anemia or thalassemia by increasing the levels of fetal hemoglobin might be effected by increasing the proportion of fetal-like erythrocytes. Fetal and fetal-like erythrocytes appear to be the end product of discrete classes of erythroid progenitors ("fetal" and "fetal-like"). The two types of progenitors are distinguished by their levels of Hb F and GGamma, as well as the correlation of these levels in single colonies. Hemoglobin switching during ontogeny could occur because of the gradual replacement of fetal by fetal-like erythroid progenitors. Increased fetal hemoglobin in patients would then result from direct amplification and maturation of the fetal-like progenitors (retaining a program for fetal Hb production). Our studies are directed at providing further evidence for the discrete differences between fetal and fetal-like erythrocytes, by examination of Hb F, GGamma, i antigen, MCV and other parameters during ontogeny and in patients with various disorders. We will examine the differences between the erythroid progenitors in the same disorders, by culturing peripheral blood or bone marrow cells in methyl cellulose with erythropoietin, and examining Hb F synthesis and the pattern of correlation of GGamma with Hb F at the level of single colonies. These studies appear to discriminate between the fetal and fetal-like adult progenitors. We will evaluate the role of cellular and soluble regulators of erythropoiesis and Hb F production, to determine those factors which would increase the production of red cells from the fetal-like progenitors.